Most of the time-of-flight mass spectrometers used today acquire individual time-of-flight spectra in rapid succession. Hundreds to several hundred thousands of these individual spectra, which are acquired at a scanning rate of five thousand to thirty thousand spectra per second, are then immediately processed into a sum time-of-flight spectrum in order to obtain useful time-of-flight spectra with well-defined ion current signals (peaks) for the ion species of different masses. A method for improving the mass resolution has been used for some time; it includes adding the intensity of the peak only at the position of the peak maximum.
From the time-of-flight spectra, mass spectra are computed, using a calibrated transformation function. The purpose of many of these time-of-flight mass spectrometers is to determine the masses of the individual ion species as accurately as possible. Significant progress has been achieved in recent years; while approximately ten years ago a mass accuracy of 10 ppm was being aimed for (but rarely achieved), today the goal of 200 ppb is realistically on the horizon. As used here, the terms “ppm” (parts per million) and “ppb” (part per billion) for the accuracy refer to the relative accuracy of mass determination in parts per million or parts per billion of the mass, i.e., the relative deviation between the mass determined from a peak and the true value, averaged over many mass determinations. The precision (or reproducibility) is set statistically as sigma, the width parameter of the distribution of repeated measurements, with a tacit assumption of a normal distribution of the measurement variance. This width parameter gives the distance on the abscissa between the point of inflection and the maximum of the Gaussian normal distribution curve.
Nowadays, the target of 200 ppb is already being achieved for the reproducibility of the calculated masses in some high-quality types of time-of-flight mass spectrometers, but strangely not yet for the mass accuracy itself, i.e., for the accuracy of the mass determination. The masses are calculated using a calibration function, which represents the masses as a function of the times of flight of the peaks. If a smooth calibration curve is used to calculate the masses, for example a power series with only a few terms, as is theoretically required and expected, the values derived for the masses of different ion species reproducibly deviate from the true values toward slightly smaller or slightly larger values. These small deviations are of the order of a few hundred ppb, and are reproduced well in successive measurements. They thus point to systematic errors, but with erratic changes of size and direction of the systematic error within small mass intervals, hitherto not explainable.
The progress made in improving the reproducibility of the mass determination is attributable to a large number of individual improvements, such as improvement to the ion optics, stability of the electronics, thermal stability of the instrument, including the flight tube, resistance to vibrations, improvements to the ion detector and an increase in the sampling rate of the ion current measurements to four or five gigahertz all contribute to these improvements.
In time-of-flight mass spectrometers of this type, secondary electron multipliers (SEM) are used, without exception, in the ion detectors to measure the ion currents. They often take the form of multichannel plates (MCP), but there are also other embodiments. The multichannel plates have millions of channels of equal diameter each, which are arranged at an angle to the plane of the plates so that the ions cannot simply fly through. There are MCPs with channels of about 2 to 8 micrometers in diameter on the market. Two channel plates are usually connected in series with the channels at offset angles in order to achieve better amplification of the electron currents. The amplification can be set to values from 105 to 107 so that a single ion generates a signal of 105 to 107 secondary electrons, which are collected on an electrode. The detectors have a complicated structure in order not to generate any signal distortions; those skilled in the art are familiar with these arrangements, so that it is not necessary to explain these detectors in more detail here. In conjunction with a post-amplifier, they can be adjusted in such a way that a single ion generates a signal that stands out significantly from the electronic noise.
The process of avalanche-like secondary electron multiplication in the individual channels of the plates also results in a broadening of the amplified signal, however. The best ion detectors currently provide an electron current which is around 500 picoseconds wide from a single impinging ion. The signal widths are around one nanosecond or more if less expensive pairs of channel plates are used. Since the technology is mature, it is not to be expected that significant progress will be made here in the future.
Special electronic digitization units can be used for the temporal sampling and digitization of the electron current, whose integral over time is proportional to the ion current to a good approximation; these units are developed out of the known transient recorders and associated digital oscillographs. Nowadays, they operate with sampling rates of four to eight gigahertz. While the processing speed of other electronic components and systems doubles roughly every 1.5 to three years, the sampling rate in the field of transient recorders has not increased for a number of years. It is, however, to be expected that the digitization depth will improve from eight to ten or even twelve bits.
These special digitization units sample the electron current from the secondary electron multipliers in a fixed measuring time raster, at a sampling rate of five gigahertz, for example. The electron current from a single ion provides a series of five to fifteen measurement values above the noise for a conventional ion detector with full widths at half-maximum of 500 to 1000 picoseconds at a sampling rate of five gigahertz. If the digitized measurement values for ions of one mass from several individual spectra are summed, or if several ions of the same mass are detected in an individual spectrum, the signal widths become larger compared to the signal of an individual ion because residual focusing errors of the mass spectrometer, uncompensated effects of the initial energy distributions of the ions before they are pulsed out, and other effects come into play. At present, these effects still result in additional signal broadenings in the order of a few nanoseconds, usually dependent on the mass of the ions.
In time-of-flight mass spectrometers with orthogonal ion injection, a special measurement procedure is used as a rule. Since there is practically no background of erratically occurring scattered ions in these mass spectrometers, each single ion is significant in the analytical sense. In order to measure each single ion with a high degree of certainty, the electronic background noise is suppressed by using a measuring threshold that is so high that electronic noise is no longer measured. The measuring threshold can either be set, for example, electronically on the digitization unit or implemented in the software of the processing method. The amplification of the SEM is then set so that a single ion produces, on average, a signal with an amplitude of 10 to 15 counts above the measurement threshold, for example. This is done so that those ions that produce only a weak signal in the SEM are also measured. Since the impact of the ions only releases a few first-generation secondary electrons, the amplitude of the signals of individual ions varies roughly in accordance with a Poisson distribution. The SEM setting means that ions which release only a single secondary electron, and thus generate a signal of low amplitude, are also measured.
This measuring procedure leads to large regions in both the individual spectra and the sum spectrum being empty, without electronic noise, and the spectra contain only the signals of analytically significant ions. If, at a given time of flight, ion signals are present in practically every individual spectrum acquired, a very high-amplitude signal is generated at this point when the individual spectra are summed; but a low-amplitude signal in the sum spectrum may contain only the signals from ions which have occurred in only every hundredth or thousandth individual spectrum. Some analytical tasks require that around ten ions of a specific mass must be found in one million summed individual mass spectra, which requires around two minutes of measuring time.
As has been briefly mentioned above, this measuring procedure can be improved to increase the time-of-flight resolution of the peaks in the sum spectra. Years of experience have shown that improving the time-of-flight resolution also improves the time-of-flight accuracy because the accuracy is approximately inversely proportional to the resolution. A rule of thumb says that the mass can be accurately determined to within around 1/20 of the width of the peak profile. The resolution of the time of flight is defined as the time of flight divided by the width of the peak at half height, measured in units of the time of flight. Although the full width at half-maximum of an individual ion's peak is only 500 to 1500 picoseconds, depending on the quality of the detector, the summing of several peaks leads to a broadening because ions of exactly the same mass do not impact on the ion detector at exactly the same time of flight due to residual focusing errors in the mass spectrometer, uncompensated effects of the initial energy distributions of the ions before they are pulsed out, and particularly due to the characteristics of the ion detectors. It does not matter here whether the ions occur simultaneously in the same individual spectrum or sequentially in different individual spectra. The broadening of the ion peaks leads to lower time-of-flight resolution and accuracy, and after the times of flight have been converted into masses, it leads to lower mass resolution and lower mass accuracy also. In order to reduce the broadening, example embodiments in U.S. Pat. No. 6,870,156 add the peak intensities obtained from the digitized sequences of measurements of a peak (or even only partial intensities, such as the intensity of the highest measured value) in the sum spectrum only at the times of flight of the maximum measurement of the peak. An ion current signal is thus obtained in the sum spectrum whose width is determined only by the variance of the times of flight of the peak maximum and no longer by the full width at half-maximum of the ion detector. In this way an increased time-of-flight resolution is achieved. The statistical variances of the position of the peak maximum mean that digitized ion current signals with sequences of several intensity values are contained in the sum spectrum. The times of flight of the peaks and the overall intensities are then determined with the aid of a suitable peak detection algorithm.
In the prior art, multichannel plates with an internal channel diameter of around six micrometers were used. Incident ions can penetrate into the channels for some distance, which results in an average penetration depth and a variation of the penetration depths. The variation of the penetration depths is around 10 micrometers. This means that the flight distances also vary by these 10 micrometers. For a total flight distance of two meters, the variations of the flight distances and thus also of the times of flight amount to five parts per million (5 ppm). Due to the quadratic relationship between mass and time of flight, this results in mass variations of ten parts per million (10 ppm). To improve this, there was first a changeover to using multichannel plates with channel diameters of two micrometers; today even secondary electron multipliers with a plane first dynode are used, whose extraordinarily high planarity results in flight distance variations of only around 0.05 micrometers, i.e., mass variations of only 0.1 ppm (100 ppb). Similar improvements are also achieved for other residual ion-optical errors.
By improving the time-of-flight mass spectrometers, the variations in the times of flight of the peaks in the individual spectra caused by residual errors in the ion optics of the instruments become smaller and smaller. Thus, even if several ions occur, the width of the peak of these ions will, in the future, deviate less and less from the signal width of the electron current of a single ion. These improvements have consequences for methods according to U.S. Pat. No. 6,870,156 if these involve the intensities being summed only at the points of the time of flight with intensity maxima. If further improvements mean that the ion-optical variances increasingly disappear, the maxima of the measurements of a peak will appear increasingly at precisely the same time of flight. In the end, signals appear in the sum spectrum, which have intensity entries only at this one single position. For the signal detection methods, this means that the technique of forming centers of gravity (centroids) over several entries in the sum spectrum can no longer be used to achieve a more exact time-of-flight determination than corresponds to the time raster of the measurements in the digitizing unit. If a digitizing unit with a 5 gigahertz measuring rate is used, the times of flight of the ions of one species can only be determined with a best accuracy of 200 picoseconds. This results in systematic errors which cannot be corrected.
The problem of incorrect masses can be explained in more detail using the digitized ion peak which is shown in FIG. 2. If this peak is reproduced identically in a mass spectrometer of ideal quality, the ion intensities are always added at measurement raster location 3 on the abscissa in accordance with an embodiment of U.S. Pat. No. 6,870,156. However, since the peak, characterized by its center of gravity (in short “centroid”), is positioned at location 2.6 on the abscissa, and the abscissa shows time-of-flight intervals of 200 picoseconds each, the addition is always carried out at a wrong position with an error of 80 picoseconds with respect to the position of the centroid. If, for example, the ions with a mass of m/z=1000 atomic mass units appear at a time of flight of 40 microseconds, a systematic error of 2 ppm results for their time of flight, and 4 ppm for the mass. This is an extremely large error given a desired mass accuracy of 200 ppb. Even if improvements to the mass spectrometers are not yet so far advanced that this maximum error occurs, nevertheless this example shows that errors of this type cannot be accepted.
Similar considerations concerning incorrect times of flight of ion current signals also apply to the method which is disclosed in U.S. Pat. No. 7,412,334.
There is a need to provide method and apparatus with which individual spectra of a time-of-flight mass spectrometer are processed to give sum spectra which have both a higher time-of-flight resolution and a better accuracy in determining the times of flight of the peaks compared to a sum spectrum comprised of summed individual spectra.